US7485452B2 - Method of making optically active ester derivatives and their acids from racemic esters - Google Patents
Method of making optically active ester derivatives and their acids from racemic esters Download PDFInfo
- Publication number
- US7485452B2 US7485452B2 US11/587,228 US58722806A US7485452B2 US 7485452 B2 US7485452 B2 US 7485452B2 US 58722806 A US58722806 A US 58722806A US 7485452 B2 US7485452 B2 US 7485452B2
- Authority
- US
- United States
- Prior art keywords
- hydroxybutyrate
- ethyl
- ester derivatives
- optically active
- racemic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
Links
- 239000002253 acid Substances 0.000 title claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 9
- 150000007513 acids Chemical class 0.000 title claims description 6
- 150000002148 esters Chemical class 0.000 title abstract description 13
- -1 β-hydroxybutyl ester Chemical class 0.000 claims abstract description 27
- 108090001060 Lipase Proteins 0.000 claims abstract description 22
- 239000004367 Lipase Substances 0.000 claims abstract description 22
- 102000004882 Lipase Human genes 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 235000019421 lipase Nutrition 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 22
- 244000005700 microbiome Species 0.000 claims abstract description 19
- 239000012074 organic phase Substances 0.000 claims abstract description 5
- 239000008346 aqueous phase Substances 0.000 claims abstract description 4
- 239000003125 aqueous solvent Substances 0.000 claims abstract description 4
- 102000004190 Enzymes Human genes 0.000 claims description 11
- 108090000790 Enzymes Proteins 0.000 claims description 11
- 241000222175 Diutina rugosa Species 0.000 claims description 8
- 239000011942 biocatalyst Substances 0.000 claims description 8
- 241000316848 Rhodococcus <scale insect> Species 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 8
- 230000003287 optical effect Effects 0.000 abstract description 6
- 230000000707 stereoselective effect Effects 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 238000007796 conventional method Methods 0.000 abstract description 2
- 240000008791 Antiaris toxicaria Species 0.000 abstract 1
- OMSUIQOIVADKIM-UHFFFAOYSA-N ethyl 3-hydroxybutyrate Chemical compound CCOC(=O)CC(C)O OMSUIQOIVADKIM-UHFFFAOYSA-N 0.000 description 18
- 229940040461 lipase Drugs 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- OMSUIQOIVADKIM-YFKPBYRVSA-N ethyl (3s)-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@H](C)O OMSUIQOIVADKIM-YFKPBYRVSA-N 0.000 description 7
- ZAJNMXDBJKCCAT-UHFFFAOYSA-N ethyl 4-chloro-3-hydroxybutanoate Chemical compound CCOC(=O)CC(O)CCl ZAJNMXDBJKCCAT-UHFFFAOYSA-N 0.000 description 7
- ZAJNMXDBJKCCAT-RXMQYKEDSA-N ethyl (3r)-4-chloro-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@@H](O)CCl ZAJNMXDBJKCCAT-RXMQYKEDSA-N 0.000 description 6
- AIZRKZQHJNWBEI-UHFFFAOYSA-N ethyl 4-bromo-3-hydroxybutanoate Chemical compound CCOC(=O)CC(O)CBr AIZRKZQHJNWBEI-UHFFFAOYSA-N 0.000 description 6
- LOQFROBMBSKWQY-UHFFFAOYSA-N ethyl 4-cyano-3-hydroxybutanoate Chemical compound CCOC(=O)CC(O)CC#N LOQFROBMBSKWQY-UHFFFAOYSA-N 0.000 description 6
- 108010084311 Novozyme 435 Proteins 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- LDLDJEAVRNAEBW-UHFFFAOYSA-N Methyl 3-hydroxybutyrate Chemical compound COC(=O)CC(C)O LDLDJEAVRNAEBW-UHFFFAOYSA-N 0.000 description 4
- UYXTWWCETRIEDR-UHFFFAOYSA-N Tributyrin Chemical compound CCCC(=O)OCC(OC(=O)CCC)COC(=O)CCC UYXTWWCETRIEDR-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 4
- 229940093858 ethyl acetoacetate Drugs 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- LHDWRKCOQQHAMP-UHFFFAOYSA-N butyl 3-hydroxybutanoate Chemical compound CCCCOC(=O)CC(C)O LHDWRKCOQQHAMP-UHFFFAOYSA-N 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- ZAJNMXDBJKCCAT-YFKPBYRVSA-N ethyl (3s)-4-chloro-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@H](O)CCl ZAJNMXDBJKCCAT-YFKPBYRVSA-N 0.000 description 3
- OMSUIQOIVADKIM-RXMQYKEDSA-N ethyl (R)-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@@H](C)O OMSUIQOIVADKIM-RXMQYKEDSA-N 0.000 description 3
- MTAYETVPZNVYFE-UHFFFAOYSA-N ethyl 4-azido-3-hydroxybutanoate Chemical compound CCOC(=O)CC(O)CN=[N+]=[N-] MTAYETVPZNVYFE-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical compound OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 101000968489 Rhizomucor miehei Lipase Proteins 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- AIZRKZQHJNWBEI-RXMQYKEDSA-N ethyl (3r)-4-bromo-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@@H](O)CBr AIZRKZQHJNWBEI-RXMQYKEDSA-N 0.000 description 2
- LOQFROBMBSKWQY-ZCFIWIBFSA-N ethyl (3r)-4-cyano-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@H](O)CC#N LOQFROBMBSKWQY-ZCFIWIBFSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- YQGDEPYYFWUPGO-GSVOUGTGSA-N (3r)-4-amino-3-hydroxybutanoic acid Chemical compound NC[C@H](O)CC(O)=O YQGDEPYYFWUPGO-GSVOUGTGSA-N 0.000 description 1
- WHBMMWSBFZVSSR-GSVOUGTGSA-M (R)-3-hydroxybutyrate Chemical compound C[C@@H](O)CC([O-])=O WHBMMWSBFZVSSR-GSVOUGTGSA-M 0.000 description 1
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
- WHBMMWSBFZVSSR-VKHMYHEASA-N (S)-3-hydroxybutyric acid Chemical compound C[C@H](O)CC(O)=O WHBMMWSBFZVSSR-VKHMYHEASA-N 0.000 description 1
- 241000194107 Bacillus megaterium Species 0.000 description 1
- AQIXEPGDORPWBJ-UHFFFAOYSA-N CCC(O)CC Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 1
- XMLIWSAJPXOFMP-FHNDMYTFSA-N CCC(O)CC.CCC(O)CC.CC[C@H](O)CC(=O)O Chemical compound CCC(O)CC.CCC(O)CC.CC[C@H](O)CC(=O)O XMLIWSAJPXOFMP-FHNDMYTFSA-N 0.000 description 1
- JIMKQLHITXEPCD-WCCKRBBISA-N CCC(O)CC.CC[C@H](O)CC(=O)O Chemical compound CCC(O)CC.CC[C@H](O)CC(=O)O JIMKQLHITXEPCD-WCCKRBBISA-N 0.000 description 1
- 102100021851 Calbindin Human genes 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000222173 Candida parapsilosis Species 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010050375 Glucose 1-Dehydrogenase Proteins 0.000 description 1
- 101000898082 Homo sapiens Calbindin Proteins 0.000 description 1
- 241001138401 Kluyveromyces lactis Species 0.000 description 1
- 101710084385 Lipase 8 Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108050006759 Pancreatic lipases Proteins 0.000 description 1
- 102000019280 Pancreatic lipases Human genes 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 101001021643 Pseudozyma antarctica Lipase B Proteins 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 241000228393 Sporidiobolus salmonicolor Species 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 229960002298 aminohydroxybutyric acid Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001384 anti-glaucoma Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 229940055022 candida parapsilosis Drugs 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- XLMHWPKLLRDGNB-UHFFFAOYSA-N diazonio-(4-ethoxy-2-hydroxy-4-oxobutan-2-yl)azanide Chemical compound CCOC(=O)CC(C)(O)N=[N+]=[N-] XLMHWPKLLRDGNB-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- MEGHWIAOTJPCHQ-UHFFFAOYSA-N ethenyl butanoate Chemical compound CCCC(=O)OC=C MEGHWIAOTJPCHQ-UHFFFAOYSA-N 0.000 description 1
- MTAYETVPZNVYFE-YFKPBYRVSA-N ethyl (3s)-4-azido-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@H](O)CN=[N+]=[N-] MTAYETVPZNVYFE-YFKPBYRVSA-N 0.000 description 1
- AIZRKZQHJNWBEI-YFKPBYRVSA-N ethyl (3s)-4-bromo-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@H](O)CBr AIZRKZQHJNWBEI-YFKPBYRVSA-N 0.000 description 1
- LOQFROBMBSKWQY-LURJTMIESA-N ethyl (3s)-4-cyano-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@@H](O)CC#N LOQFROBMBSKWQY-LURJTMIESA-N 0.000 description 1
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 1
- YQGDEPYYFWUPGO-UHFFFAOYSA-N gamma-amino-beta-hydroxybutyric acid Chemical compound [NH3+]CC(O)CC([O-])=O YQGDEPYYFWUPGO-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000006458 gyp medium Substances 0.000 description 1
- 108010084715 isopropanol dehydrogenase (NADP) Proteins 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229940116369 pancreatic lipase Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003016 pheromone Substances 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
- G02B6/0001—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings specially adapted for lighting devices or systems
- G02B6/0011—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings specially adapted for lighting devices or systems the light guides being planar or of plate-like form
- G02B6/0033—Means for improving the coupling-out of light from the light guide
- G02B6/005—Means for improving the coupling-out of light from the light guide provided by one optical element, or plurality thereof, placed on the light output side of the light guide
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/001—Amines; Imines
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/002—Nitriles (-CN)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/62—Carboxylic acid esters
-
- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
- G02B6/0001—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings specially adapted for lighting devices or systems
- G02B6/0011—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings specially adapted for lighting devices or systems the light guides being planar or of plate-like form
- G02B6/0033—Means for improving the coupling-out of light from the light guide
- G02B6/0058—Means for improving the coupling-out of light from the light guide varying in density, size, shape or depth along the light guide
- G02B6/0061—Means for improving the coupling-out of light from the light guide varying in density, size, shape or depth along the light guide to provide homogeneous light output intensity
-
- G—PHYSICS
- G02—OPTICS
- G02F—OPTICAL DEVICES OR ARRANGEMENTS FOR THE CONTROL OF LIGHT BY MODIFICATION OF THE OPTICAL PROPERTIES OF THE MEDIA OF THE ELEMENTS INVOLVED THEREIN; NON-LINEAR OPTICS; FREQUENCY-CHANGING OF LIGHT; OPTICAL LOGIC ELEMENTS; OPTICAL ANALOGUE/DIGITAL CONVERTERS
- G02F1/00—Devices or arrangements for the control of the intensity, colour, phase, polarisation or direction of light arriving from an independent light source, e.g. switching, gating or modulating; Non-linear optics
- G02F1/01—Devices or arrangements for the control of the intensity, colour, phase, polarisation or direction of light arriving from an independent light source, e.g. switching, gating or modulating; Non-linear optics for the control of the intensity, phase, polarisation or colour
- G02F1/13—Devices or arrangements for the control of the intensity, colour, phase, polarisation or direction of light arriving from an independent light source, e.g. switching, gating or modulating; Non-linear optics for the control of the intensity, phase, polarisation or colour based on liquid crystals, e.g. single liquid crystal display cells
- G02F1/133—Constructional arrangements; Operation of liquid crystal cells; Circuit arrangements
- G02F1/1333—Constructional arrangements; Manufacturing methods
- G02F1/133342—Constructional arrangements; Manufacturing methods for double-sided displays
Definitions
- the present invention relates to a process for the preparation of optically active ⁇ -hydroxybutyl ester derivatives and their acid derivatives.
- this invention relates to the process for preparing optically active ⁇ -hydroxybutyl ester derivatives and their acid derivatives by the hydrolysis of racemic ⁇ -hydroxybutyl ester derivatives represented by the general formula 1 in scheme 1 using lipases or lipase-producing microorganisms.
- optically active ⁇ -hydroxybutyl ester derivatives and their acid derivatives can be used intensively as important chiral intermediates.
- ⁇ -hydroxybutyl ester derivatives and their acid derivatives produced by this invention have high optical purity and this method can be used in practical process because separation and recovery of the products are easy. Therefore this invention can be used on the industrial scale.
- ethyl (R)-3-hydroxybutyrate is an intermediate for an anti-glaucoma drug (Chirality in industry ⁇ . Chichester, UK:Wiley, 1997, 245-262) and (S)-3-hydroxybutyrate is used for synthesizing pheromones (Tertahedron, 1989, 45:3233-3298) and carbapenems (Journal of the Chemical Society. Perkin Transaction, 1999, 1: 2489-2494).
- ethyl (R)-4-chloro-3-hydroxybutyrate is used for synthesizing L-carnitine(Journal of the American Chemical Society, 1983, 105:5925-5926), (R)-4-amino-3-hydroxybutyric acid (GABOB) and (R)-hydroxy-2-pyrrolidone.
- Ethyl (S)-4-chloro-3-hydroxybutyrate is a valuable synthon for the production of hydroxyymethylglutaryl CoA (HMG-CoA) reductase inhibitor (Journal of Medicinal Chemistry, 1990, 33:2952-2956).
- Ethyl (S)-3-hydroxybutyrate is synthesized by asymmetric hydrogenation of ethylacetoacetate using BINAP-coordinated Ru(II) complexes (Journal of the American Chemical Society, 1987, 109:5856-5858).
- this method has disadvantages of high pressure during the reaction and high cost of metal catalyst.
- ethyl (R)-3-hydroxybutyrate can be prepared by acidic alcoholysis of Poly-(R)-3-hydroxybutyrate accumulated by microorganisms (Enzyme and Microbial Technology, 2000, 27:33-36).
- Optically active ethyl 4-chloro-3-hydroxybutyrate can be produced by reduction of ethyl 4-chloroacetoacetate.
- Matsuyama et al. Japan Kokai Tokkyo Koho, 06-209782, Aug. 2, 1994
- ethyl (S)-4-chloro-3-hydroxybutyrate 97% yield, 98% e.e) using Kluyveromyces lactis NRIC 1329.
- Yamamoto et al. (Bioscience Biotechnology and Biochemistry, 2002, 66(2):481-483) produced ethyl (R)-4-chloro-3-hydroxybutyrate (95.2% conversion, 99% e.e) using recombinant microorganism expressing secondary alcohol dehydrogenase from Candida parapsilosis .
- these methods have disadvantage of long reaction time.
- Hoff et al. (Tetrahedron:Asymmetry, 1999, 10:1401-1412) obtained ethyl (S)-4-chlro-3-hydroxybutyrate (24% yield, 86% e.e) by transesterifying for 5 days using Rhizomucor miehei lipase (RML) in organic phase (benzene).
- RML Rhizomucor miehei lipase
- Suzuki et al. (Enzyme Microbiology and Technology, 1999, 24:13-20) produced ethyl (R)-4-chloro-3-hydroxybutyrate (99.8% e.e) using dechlorinase-producing microorganism.
- optically active ⁇ -hydroxybutyl ester derivatives can be prepared by the stereoselective reduction of keto esters or the enzymatic transesterification.
- these methods are not suitable due to their disadvantages including low enantiomeric excess, low yield or difficulties in the separation of products and reactants after reaction.
- hydrolysis of ⁇ -hydroxybutyl ester derivatives Santaniello et al.(Gazzetta Chemica Italiana, 1989, 119:581-584) obtained ethyl (R)-4-chloro-3-hydroxybutyrate and (S)-their acid by hyrolysis of ethyl 4-chloro-3-hydroxybutyrate using pig liver esterase.
- this method has disadvantages of low yield (23%) and low enantiomeric excess (16% e.e) and is not suitable for industrial use.
- This method is simple and ester derivatives and their acid derivatives of higher optical purity can be obtained comparing to the conventional methods.
- the objective of this invention is to provide the method of preparing optically active esters and their acids from racemic ⁇ -hydroxybutyl ester derivatives using enzymes or microorganisms.
- the present invention consists of the process for preparing high optically active ⁇ -hydroxybutyl ester derivatives and their acids from racemic ⁇ -hydroxybutyl ester derivatives by stereospecific hydrolysis using lipases or lipase-producing microorganisms as biocatalysts in aqueous phase or organic phase including aqueous solvent.
- this invention relates to the process for preparing optically active ⁇ -hydroxybutyl ester derivatives and their acid derivatives by stereospecific hydrolysis of racemic ⁇ -hydroxybutyl ester derivatives using lipases or lipase-producing microorganisms as biocatalysts in aqueous phase or organic phase including aqueous solvent.
- methyl 3-hydroxybutyrate, ethyl 3-hydroxybutyrate, butyl 3-hydroxybutyrate, ethyl 3-azido-3-hydroxybutyrate, ethyl 4-chloro-3-hydroxybutyrate, ethyl 4-bromo-3-hydroxybutyrate and ethyl 4-cyano-3-hydroxybutyrate are used as racemic ⁇ -hydroxybutyl esters, but the reactant is not restricted to them.
- Non-limiting examples of the commercially available lipases include PS lipase from Amano Inc., Candida rugosa lipase and Novozyme 435 and non-limiting examples of the lipase-producing microorganism include Candida rugosa and Rhodococcus butanica.
- optically active esters and their acids are separated respectively by solvent extraction method or column chromatography.
- racemic compounds were determined by gas chromatography (Donam Instrument Inc. Model 6200) equipped with HP-FFAP (Agilent, Inc., 30 mm ⁇ 0.53 m) column. The oven temperature was maintained initially at 70° C. for 5 min and then raised at the rate of 10° C./min to 220° C., and maintained for 10 minutes. Helium gas is used as carrier at the rate of 2 ml/min, and compounds were detected using FID detector.
- the typical retention time of the components in this invention were as follows:
- Racemic ethyl 4-bromo-3-hydroxybutyrate and racemic ethyl 4-cyano-3-hydroxybutyrate were analyzed using the same method used in the analysis of racemic methyl 3-hydroxybutyrate except that oven temperature was increased at 20° C./min. In this condition racemic ethyl 4-bromo-3-hydroxybutyrate and racemic ethyl 4-cyano-3-hydroxybutyrate are detected at 11.7 min and 14.07 min respectively.
- Optically active methyl 3-hydroxybutyrate, ethyl 3-hydroxybutyrate, butyl 3-hydroxybutyrate and ethyl 4-azido-3-hydroxybutyrate were determined by HPLC (Waters, Inc., Model 1525) equipped with chial column OD-H (Daicel, 0.46 cm ⁇ 25 cm) using hexane and isopropyl alcohol mixture (90:10) as mobile phase.
- the absorbance was 220 nm and flow rate was 0.7 ml/min.
- the typical retention time of the components in this invention was as follows:
- Optically active ethyl 4-cyano-3-hydroxybutyrate was determined by a gas chromatography(Donam Instrument Inc. Model 6200) equipped with chiral column G-TA(Astec, 30 mm ⁇ 0.32 m). The oven temperature was maintained initially at 100° C. for 5 min and then raised to 170° C. at the rate of 10° C./min, and maintained for 20 minutes. Helium gas was used as carrier gas and column head pressure was maintained at 10 psi, and compounds were detected using FID detector. In this condition, the typical retention time of ethyl (R)-4-cyano-3-hydroxybutyrate and ethyl (S)-4-cyano-3-hydroxybutyrate was 16.75 min and 16.53 min respectively.
- Optically active ethyl 4-chloro-3-hydroxybutyrate was determined by a HPLC (Lab Alliance, Model 201) equipped with chial column OB-H (Daicel, 0.46 cm ⁇ 25 cm) using hexane and isopropyl alcohol mixture (95:5) as mobile phase. The flow rate was 0.7 ml/min and absorbance was 215 nm. The typical retention time of ethyl (R)-4-chloro-3-hydroxybutyrate and ethyl (S)-4-chloro-3-hydroxybutyrate was 14.42 min and 15.38 min, respectively.
- Optically active ethyl 4-bromo-3-hydroxybutyrate was determined by a HPLC (Lab Alliance, Model 201) equipped with chial column AD-H(Daicel, 0.46 cm ⁇ 25 cm) using hexane and isopropyl alcohol mixture (90:10) as mobile phase. The flow rate was 0.7 ml/min and absorbance was 220 nm. In this condition, the typical retention time of ethyl (R)-4-bromo-3-hydroxybutyrate and ethyl (S)-4-bromo-3-hydroxybutyrate was 12.23 min and 11.24 min, respectively.
- Racemic ethyl 3-hydroxybutyrate (1%, v/v) was added to the vial containing 5 ml potassium phosphate buffer (pH 8.0, 0.1 M) and Novozyme 435 (4%, w/v). The reaction was carried out at 30° C. for 2 hours. The reaction mixture was extracted with ethyl acetate and analyzed by above-mentioned method. Ethyl (S)-3-hydroxybutyrate (97% e.e) was obtained from organic solvent at 55% conversion. The aqueous solution was acidified with hydrochloric acid and extracted with organic solvent. After esterification, ethyl (R)-3-hydroxybutyrate with optical purity of 80.4% e.e was obtained.
- Lipase-producing microorganisms were isolated by cultivating in a medium containing 1% tributyrin. Isolated strains assimilated tributyrin and made clear zone. The strains were grown in LB medium or GYP medium including glucose, and microorganisms were harvested by centrifuge and used as biocatalysts. The results are shown in Table 1.
- ethyl 4-azido-3-hydroxybutyrate was used instead of ethyl 3-hydroxybutyrate used in Example 1. The reaction was carried out for 1 hour and ethyl (S)-4-azido-3-hydroxybutyrate (80.2% e.e) was obtained at 83.5% conversion.
- ethyl 4-bromo-3-hydroxybutyrate 1%, w/v
- novozyme 435 lipase was used as a biocatalyst.
- ethyl (R)-4-bromo-3-hydroxybutyrate 99% e.e was obtained at 88.3% conversion.
- ethyl 4-cyano-3-hydroxybutyrate 1%, w/v
- novozyme 435 lipase was used as a biocatalyst.
- ethyl (R)-4-cyano-3-hydroxybutyrate 99% e.e was obtained at 57.3% conversion.
- optically active ⁇ -hydroxybutyl ester derivatives can be produced easily by hydrolysis of this invention. With appropriate lipases or microorganisms, ⁇ -hydroxybutyl ester derivatives of high optical purity can be produced. Also, it is easy to separate optically active esters from their acids after reaction. Therefore, this method is a useful process on the industrial scale.
Abstract
The present invention relates to process for the preparing of optically active ester derivatives and their acid derivatives which are used intensively as important chiral intermediates from racemic β-hydroxybutyl ester derivatives. In more detail, this invention relates to the process for preparing optically active β-hydroxybutyl ester derivatives and their acid derivatives by stereospecific hydrolysis of racemic β-hydroxybutyl ester derivatives using Upases or lipase-producing microorganisms in the aqueous phase or organic phase including aqueous solvent. The method of making optically active ester derivatives and their acid derivatives by hydrolysis of β-hydroxybutyl ester derivatives represented by the general formula 1 in scheme 1 is easier and more economical comparing to the conventional methods and the products have high optical purity. Also separation of ester derivatives from acid derivatives is easy after reaction. Thus this method is a useful process on the industrial scale.
Description
The present invention relates to a process for the preparation of optically active β-hydroxybutyl ester derivatives and their acid derivatives. In more detail, this invention relates to the process for preparing optically active α-hydroxybutyl ester derivatives and their acid derivatives by the hydrolysis of racemic α-hydroxybutyl ester derivatives represented by the general formula 1 in scheme 1 using lipases or lipase-producing microorganisms.
The above-mentioned optically active α-hydroxybutyl ester derivatives and their acid derivatives can be used intensively as important chiral intermediates. Also, α-hydroxybutyl ester derivatives and their acid derivatives produced by this invention have high optical purity and this method can be used in practical process because separation and recovery of the products are easy. Therefore this invention can be used on the industrial scale.
According to a report, ethyl (R)-3-hydroxybutyrate is an intermediate for an anti-glaucoma drug (Chirality in industry Π. Chichester, UK:Wiley, 1997, 245-262) and (S)-3-hydroxybutyrate is used for synthesizing pheromones (Tertahedron, 1989, 45:3233-3298) and carbapenems (Journal of the Chemical Society. Perkin Transaction, 1999, 1: 2489-2494).
And ethyl (R)-4-chloro-3-hydroxybutyrate is used for synthesizing L-carnitine(Journal of the American Chemical Society, 1983, 105:5925-5926), (R)-4-amino-3-hydroxybutyric acid (GABOB) and (R)-hydroxy-2-pyrrolidone. Ethyl (S)-4-chloro-3-hydroxybutyrate is a valuable synthon for the production of hydroxyymethylglutaryl CoA (HMG-CoA) reductase inhibitor (Journal of Medicinal Chemistry, 1990, 33:2952-2956).
There are several methods to prepare optically active β-hydroxybutyl ester derivatives. Ethyl (S)-3-hydroxybutyrate is synthesized by asymmetric hydrogenation of ethylacetoacetate using BINAP-coordinated Ru(II) complexes (Journal of the American Chemical Society, 1987, 109:5856-5858). However, this method has disadvantages of high pressure during the reaction and high cost of metal catalyst.
Another method is the reduction of 3-oxo-esters using microorganisms. Jayasinghe et al. (Tetrahedron Letters, 1993, 34:3949-3950) obtained ethyl (S)-3-hydroxybutyrate (58% yield, 94% e.e) by the reduction of ethyl acetoacetate using freeze-dried yeast in petroleum ether and Medson et al.(Tetrahedron:Asymmetry, 1997, 8:1049-1054) obtained ethyl (S)-3-hydroxybutyrate (yield 69%, 99% e.e) from ethyl acetoacetate by the reduction using yeast in organic solvent. Chin-Joe et al.(Biotechnology and Bioengineering, 2000, 69:370-376) obtained ethyl (S)-3-hydroxybutyrate (99% e.e) at 85% conversion by the reduction of ethyl acetoacetate using Baker's yeast. However, these methods have disadvantages of low yield and purification problem after reaction.
On the other hand, Sugai et al.(Agricultural and Biological Chemistry, 1989, 53:2009-2010) obtained ethyl (S)-3-hydroxybutyrate (99.4% e.e) by transesterification of racemic ethyl 3-hydroxybutyrate using vinyl butanoate as an acylating agent and porcine pancreatic lipase as a catalyst. Fishman et al.(Biotechnology and Bioengineering, 2001, 74:256-263) obtained ethyl (S)-3-hydroxybutyrate (40% yield, 99.4% e.e) using CALB (Candida antartica) lipaseand vinyl acetate as an acyl donor.
In another case, ethyl (R)-3-hydroxybutyrate can be prepared by acidic alcoholysis of Poly-(R)-3-hydroxybutyrate accumulated by microorganisms (Enzyme and Microbial Technology, 2000, 27:33-36).
Optically active ethyl 4-chloro-3-hydroxybutyrate can be produced by reduction of ethyl 4-chloroacetoacetate. Matsuyama et al.(Japan Kokai Tokkyo Koho, 06-209782, Aug. 2, 1994) obtained ethyl (S)-4-chloro-3-hydroxybutyrate (97% yield, 98% e.e) using Kluyveromyces lactis NRIC 1329. Kataoka et al.(Applied microbiology and Biotechnology, 1999, 51:486-490) obtained ethyl (R)-4-chloro-3-hydroxybutyrate (94% yield, 92% e.e) using recombinant microorganism, which coexpress both the alcohol reductase Igene from Sporobolomyces salmonicolor and the glucose dehydrogenase gene from Bacillus megaterium. Yamamoto et al.(Bioscience Biotechnology and Biochemistry, 2002, 66(2):481-483) produced ethyl (R)-4-chloro-3-hydroxybutyrate (95.2% conversion, 99% e.e) using recombinant microorganism expressing secondary alcohol dehydrogenase from Candida parapsilosis. However, these methods have disadvantage of long reaction time.
On the other hand, Hoff et al.(Tetrahedron:Asymmetry, 1999, 10:1401-1412) obtained ethyl (S)-4-chlro-3-hydroxybutyrate (24% yield, 86% e.e) by transesterifying for 5 days using Rhizomucor miehei lipase (RML) in organic phase (benzene).
Suzuki et al.(Enzyme Microbiology and Technology, 1999, 24:13-20) produced ethyl (R)-4-chloro-3-hydroxybutyrate (99.8% e.e) using dechlorinase-producing microorganism.
As previously stated, optically active β-hydroxybutyl ester derivatives can be prepared by the stereoselective reduction of keto esters or the enzymatic transesterification. However, these methods are not suitable due to their disadvantages including low enantiomeric excess, low yield or difficulties in the separation of products and reactants after reaction. For solving these problems, there is hydrolysis of α-hydroxybutyl ester derivatives. Santaniello et al.(Gazzetta Chemica Italiana, 1989, 119:581-584) obtained ethyl (R)-4-chloro-3-hydroxybutyrate and (S)-their acid by hyrolysis of ethyl 4-chloro-3-hydroxybutyrate using pig liver esterase. However, this method has disadvantages of low yield (23%) and low enantiomeric excess (16% e.e) and is not suitable for industrial use.
Technical Problem
The process for preparing of β-hydroxybutyl ester derivatives and their acid derivatives of high optical purity was developed from racemic β-hydroxybutyl ester derivatives represented by the general formula 1 in scheme 1 by stereospecific hydrolysis using lipases or lipase-producing microorganisms.
This method is simple and ester derivatives and their acid derivatives of higher optical purity can be obtained comparing to the conventional methods.
Accordingly, the objective of this invention is to provide the method of preparing optically active esters and their acids from racemic β-hydroxybutyl ester derivatives using enzymes or microorganisms.
For the above objectives, the present invention consists of the process for preparing high optically active β-hydroxybutyl ester derivatives and their acids from racemic β-hydroxybutyl ester derivatives by stereospecific hydrolysis using lipases or lipase-producing microorganisms as biocatalysts in aqueous phase or organic phase including aqueous solvent.
Technical Solution
This invention is explained in more detail as follows. As mentioned above, this invention relates to the process for preparing optically active β-hydroxybutyl ester derivatives and their acid derivatives by stereospecific hydrolysis of racemic β-hydroxybutyl ester derivatives using lipases or lipase-producing microorganisms as biocatalysts in aqueous phase or organic phase including aqueous solvent.
In this invention, methyl 3-hydroxybutyrate, ethyl 3-hydroxybutyrate, butyl 3-hydroxybutyrate, ethyl 3-azido-3-hydroxybutyrate, ethyl 4-chloro-3-hydroxybutyrate, ethyl 4-bromo-3-hydroxybutyrate and ethyl 4-cyano-3-hydroxybutyrate are used as racemic β-hydroxybutyl esters, but the reactant is not restricted to them. In the general formula 1 in scheme 1, X is H, CN, N3, F, Cl, Br or I and R is CnH2n+1 (n=1˜8).
Non-limiting examples of the commercially available lipases include PS lipase from Amano Inc., Candida rugosa lipase and Novozyme 435 and non-limiting examples of the lipase-producing microorganism include Candida rugosa and Rhodococcus butanica.
After reaction, optically active esters and their acids are separated respectively by solvent extraction method or column chromatography.
In this invention, racemic compounds were determined by gas chromatography (Donam Instrument Inc. Model 6200) equipped with HP-FFAP (Agilent, Inc., 30 mm×0.53 m) column. The oven temperature was maintained initially at 70° C. for 5 min and then raised at the rate of 10° C./min to 220° C., and maintained for 10 minutes. Helium gas is used as carrier at the rate of 2 ml/min, and compounds were detected using FID detector. The typical retention time of the components in this invention were as follows:
racemic methyl 3-hydroxybutyrate-15.48 min
racemic ethyl 3-hydroxybutyrate-14.32 min
racemic butyl 3-hydroxybutyrate-17.16 min
racemic ethyl 4-azido-3-hydroxybutyrate-22.50 min
racemic ethyl 4-chloro-3-hydroxybutyrate-20.31 min
Racemic ethyl 4-bromo-3-hydroxybutyrate and racemic ethyl 4-cyano-3-hydroxybutyrate were analyzed using the same method used in the analysis of racemic methyl 3-hydroxybutyrate except that oven temperature was increased at 20° C./min. In this condition racemic ethyl 4-bromo-3-hydroxybutyrate and racemic ethyl 4-cyano-3-hydroxybutyrate are detected at 11.7 min and 14.07 min respectively.
Optically active methyl 3-hydroxybutyrate, ethyl 3-hydroxybutyrate, butyl 3-hydroxybutyrate and ethyl 4-azido-3-hydroxybutyrate were determined by HPLC (Waters, Inc., Model 1525) equipped with chial column OD-H (Daicel, 0.46 cm×25 cm) using hexane and isopropyl alcohol mixture (90:10) as mobile phase. The absorbance was 220 nm and flow rate was 0.7 ml/min. The typical retention time of the components in this invention was as follows:
methyl (R)-3-hydroxybutyrate-10.28 min
methyl (S)-3-hydroxybutyrate-12.44 min
ethyl (R)-3-hydroxybutyrate-12.77 min
ethyl (S)-3-hydroxybutyrate-11.43 min
butyl (R)-3-hydroxybutyrate-9.4 min
butyl (S)-3-hydroxybutyrate-10.64 min
ethyl (R)-4-azido-3-hydroxybutyrate-8.7 min
ethyl (S)-4-azido-3-hydroxybutyrate-10.86 min
Optically active ethyl 4-cyano-3-hydroxybutyrate was determined by a gas chromatography(Donam Instrument Inc. Model 6200) equipped with chiral column G-TA(Astec, 30 mm×0.32 m). The oven temperature was maintained initially at 100° C. for 5 min and then raised to 170° C. at the rate of 10° C./min, and maintained for 20 minutes. Helium gas was used as carrier gas and column head pressure was maintained at 10 psi, and compounds were detected using FID detector. In this condition, the typical retention time of ethyl (R)-4-cyano-3-hydroxybutyrate and ethyl (S)-4-cyano-3-hydroxybutyrate was 16.75 min and 16.53 min respectively.
Optically active ethyl 4-chloro-3-hydroxybutyrate was determined by a HPLC (Lab Alliance, Model 201) equipped with chial column OB-H (Daicel, 0.46 cm×25 cm) using hexane and isopropyl alcohol mixture (95:5) as mobile phase. The flow rate was 0.7 ml/min and absorbance was 215 nm. The typical retention time of ethyl (R)-4-chloro-3-hydroxybutyrate and ethyl (S)-4-chloro-3-hydroxybutyrate was 14.42 min and 15.38 min, respectively.
Optically active ethyl 4-bromo-3-hydroxybutyrate was determined by a HPLC (Lab Alliance, Model 201) equipped with chial column AD-H(Daicel, 0.46 cm×25 cm) using hexane and isopropyl alcohol mixture (90:10) as mobile phase. The flow rate was 0.7 ml/min and absorbance was 220 nm. In this condition, the typical retention time of ethyl (R)-4-bromo-3-hydroxybutyrate and ethyl (S)-4-bromo-3-hydroxybutyrate was 12.23 min and 11.24 min, respectively.
And racemic compounds were confirmed by FT-NMR (Burker, Model DRX300 or JEOL, Model AR400) and the results are as follows:
ethyl 4-azido-3-hydroxybutyrate:
1H-NMR (CDCl3, 300 MHz) δ(ppm)=1.28 (t, 3H), 2.53 (m, 2H), 3.28 (d, 1H), 3.34 (m, 2H), 4.21 (q, 2H)
ethyl 4-chloro-3-hydroxybutyrate:
1H-NMR (CDCl3, 400 MHz) δ(ppm)=1.28 (t, 3H), 2.62 (d, 2H), 3.53 (br, 1H), 3.60 (d, 2H), 4.20 (q, 2H), 4.33 (m, 1H)
ethyl 4-bromo-3-hydroxybutyrate:
1H-NMR (CDCl3, 400 MHz) δ(ppm)=1.28 (t, 3H), 2.7 (m, 2H), 3.48 (dd, 1H), 3.51 (dd, 1H), 4.17 (q, 2H), 4.20 (m, 1H)
ethyl 4-cyano-3-hydroxybutyrate:
1H-NMR (CDCl3, 300 MHz) δ(ppm)=1.26 (t, 3H), 2.5˜2.7 (m, 4H), 4.18 (q, 2H), 4.32 (m, 1H)
A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as the limit of the present invention.
Racemic ethyl 3-hydroxybutyrate (1%, v/v) was added to the vial containing 5 ml potassium phosphate buffer (pH 8.0, 0.1 M) and Novozyme 435 (4%, w/v). The reaction was carried out at 30° C. for 2 hours. The reaction mixture was extracted with ethyl acetate and analyzed by above-mentioned method. Ethyl (S)-3-hydroxybutyrate (97% e.e) was obtained from organic solvent at 55% conversion. The aqueous solution was acidified with hydrochloric acid and extracted with organic solvent. After esterification, ethyl (R)-3-hydroxybutyrate with optical purity of 80.4% e.e was obtained.
Instead of lipase used in Example 1, whole cells (20% (w/v)) were used. Lipase-producing microorganisms were isolated by cultivating in a medium containing 1% tributyrin. Isolated strains assimilated tributyrin and made clear zone. The strains were grown in LB medium or GYP medium including glucose, and microorganisms were harvested by centrifuge and used as biocatalysts. The results are shown in Table 1.
| TABLE 1 | |||||
| Con- | % e.e | ||||
| Reaction | version | for | Con- | ||
| Example | Microorgnism | time(hr) | (%) | ester | figuration |
| 2 | Candida rugosa | 62 | 69.6 | 99 | S |
| KCCM 50521 | |||||
| 3 | Rhodococcus | 3.5 | 63.9 | 99 | S |
| butanica ATCC | |||||
| 21197 | |||||
Instead of ethyl 3-hydroxybutyrate used in Example 1, 1% methyl 3-hydroxybutyrate and 5% butyl 3-hydroxybutyrate were used as reactants. The reaction was carried out with novozyme 435 lipase and the results are shown in Table 2.
| TABLE 2 | |||||
| Con- | % e.e | ||||
| Reaction | version | for | Con- | ||
| Example | Reactant | time(hr) | (%) | ester | figuration |
| 4 | methyl 3- | 5 | 78.0 | 98.8 | S |
| hydroxybutyrate | |||||
| 5 | butyl 3- | 6 | 82.0 | 78.5 | S |
| hydroxybutyrate | |||||
Instead of ethyl 3-hydroxybutyrate used in Example 1, ethyl 4-azido-3-hydroxybutyrate was used. The reaction was carried out for 1 hour and ethyl (S)-4-azido-3-hydroxybutyrate (80.2% e.e) was obtained at 83.5% conversion.
Instead of ethyl 3-hydroxybutyrate used in Example 1, ethyl 4-chloro-3-hydroxybutyrate was used as a reactant and lipases were used as biocatalysts. The results are shown in Table 3.
| TABLE 3 | |||||
| Con- | % e.e | ||||
| Reaction | version | for | Con- | ||
| Example | Lipase | time(hr) | (%) | ester | figuration |
| 7 | Pseudomonas | 22 | 71.0 | 99 | S |
| cepatia lipase | |||||
| 8 | Candida rugosa | 32 | 76.0 | 99 | R |
| lipase | |||||
Instead of ethyl 3-hydroxybutyrate used in Example 1, ethyl 4-bromo-3-hydroxybutyrate (1%, w/v) was used as a reactant and novozyme 435 lipase was used as a biocatalyst. After reaction for 1 hour 40 minutes, ethyl (R)-4-bromo-3-hydroxybutyrate (99% e.e) was obtained at 88.3% conversion.
Instead of ethyl 3-hydroxybutyrate used in Example 1, ethyl 4-cyano-3-hydroxybutyrate (1%, w/v) was used as a reactant and novozyme 435 lipase was used as a biocatalyst. After reaction for 3 hours, ethyl (R)-4-cyano-3-hydroxybutyrate (99% e.e) was obtained at 57.3% conversion.
Instead of ethyl 3-hydroxybutyrate used in Example 2, ethyl 4-chloro-3-hydroxybutyrate was used as a reactant and microorganisms in Table 4 were used as biocatalysts. The results are shown in Table 4.
| TABLE 4 | |||||
| Con- | % e.e | ||||
| Reaction | version | for | Con- | ||
| Example | Microorganism | time (hr) | (%) | ester | figuration |
| 11 | Candida rugosa | 32 | 76.1 | 99 | S |
| KCTC 7292 | |||||
| 12 | Candida rugosa | 47 | 77.3 | 99 | S |
| KCCM 50521 | |||||
| 13 | Rhodococcus | 8 | 76.1 | 99 | R |
| butanica ATCC | |||||
| 21197 | |||||
In accordance with Examples 1-13, optically active β-hydroxybutyl ester derivatives can be produced easily by hydrolysis of this invention. With appropriate lipases or microorganisms, β-hydroxybutyl ester derivatives of high optical purity can be produced. Also, it is easy to separate optically active esters from their acids after reaction. Therefore, this method is a useful process on the industrial scale.
Claims (2)
1. A process for preparing optically active β-hydroxybutyl ester derivatives and their acids derivatives from a racemic β-hydroxybutyl ester derivative, the process comprising reacting a mixture of a racemic β-hydroxybutyl ester derivative of the formula (1)
and a lipase or lipase-producing microorganism as a biocatalyst, the reaction being carried out in the aqueous phase or organic phase including aqueous solvent and providing a β-hydroxybutyl ester derivative of the formula (2) and a β-hydroxybutyl acid derivative of the formula (3),
wherein R is CnH2n+1,(n=1˜8) and X is H, N3, CN, F, Cl, Br or I.
2. A process according to claim 1 , wherein the reaction mixture comprises a lipase-producing microorganism selected from Candida rugosa KCTC 7292, Candida rugosa KCCM 5521, or Rhodococcus butanica ATCC 21197.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020040029791A KR100657212B1 (en) | 2004-04-29 | 2004-04-29 | The method of making optically active ester derivatives and their acids from racemic esters |
| KR10-2004-0029791 | 2004-04-29 | ||
| PCT/KR2005/001213 WO2005111227A1 (en) | 2004-04-29 | 2005-04-27 | The method of making optically active ester derivatives and their acids from racemic esters |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| US20080038802A1 US20080038802A1 (en) | 2008-02-14 |
| US7485452B2 true US7485452B2 (en) | 2009-02-03 |
Family
ID=35394166
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US11/587,228 Expired - Fee Related US7485452B2 (en) | 2004-04-29 | 2005-04-27 | Method of making optically active ester derivatives and their acids from racemic esters |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US7485452B2 (en) |
| EP (1) | EP1740714A1 (en) |
| KR (1) | KR100657212B1 (en) |
| CN (1) | CN1946855A (en) |
| WO (1) | WO2005111227A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9163202B2 (en) | 2013-08-02 | 2015-10-20 | Eastman Chemical Company | Aqueous cleaning compositions including an alkyl 3-hydroxybutyrate |
| US9249378B2 (en) | 2013-08-02 | 2016-02-02 | Eastman Chemical Company | Aqueous cleaning compositions having enhanced properties |
| US9255059B2 (en) | 2013-08-02 | 2016-02-09 | Eastman Chemical Company | Method for producing an alkyl 3-hydroxybutyrate |
| US9388114B2 (en) | 2013-08-02 | 2016-07-12 | Eastman Chemical Company | Compositions including an alkyl 3-hydroxybutyrate |
| US10508070B1 (en) * | 2018-11-28 | 2019-12-17 | Shanghai Shine High International Trade Co., Ltd. | Method for preparing 3-hydroxybutyrate salts |
| WO2023278240A1 (en) | 2021-06-28 | 2023-01-05 | Phb Industrial S.A. | Methods to produce therapeutic formulations comprising hydroxybutirate and hydroxyvalerate, therapeutic formulations and uses thereof |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL159719A0 (en) | 2001-07-06 | 2004-06-20 | Teva Pharma | Process for the preparation of 7-amino syn 3,5-dihydroxy heptanoic acid derivatives via 6-cyano syn 3,5-dihydroxy hexanoic acid derivatives |
| CN1948499B (en) * | 2006-05-26 | 2010-12-08 | 江南大学 | Method of preparing (R) 4,4,4-trifluoro 3-hydroxy ethyl butyrate by biocatalytic reaction |
| KR100893763B1 (en) | 2007-08-29 | 2009-04-20 | 한국화학연구원 | Method for preparing optically active alkyl 3-hydroxybutanoate derivatives |
| CN102321690B (en) * | 2011-07-27 | 2012-07-18 | 陆宏国 | Preparation method of ester chiral amines |
| CN104313064A (en) * | 2014-10-01 | 2015-01-28 | 青岛科技大学 | Method for producing chiral bromophenyl methyl propionate by virtue of cell method |
| CN105543191B (en) * | 2016-02-24 | 2019-06-21 | 中国科学院南海海洋研究所 | A kind of esterase PHE21 and its encoding gene and application |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4957867A (en) | 1986-05-29 | 1990-09-18 | Sumitomo Chemical Company, Limited | Production of cyclopentenones by enzyme resolution |
| US5108916A (en) | 1989-06-05 | 1992-04-28 | Rhone-Poulenc Rorer, S.A. | Process for stereoselectively hydrolyzing, transesterifying or esterifying with immobilized isozyme of lipase from candida rugosa |
| KR20000059531A (en) | 1999-03-04 | 2000-10-05 | 조생현 | Method for manufacturing the pirdo-benz-oxizine for optical a ativity |
| EP1408107A2 (en) | 2002-10-07 | 2004-04-14 | Daiso Co., Ltd. | Chlorohydrin and hydroxycarboxylic ester asymmetric hydrolase gene |
-
2004
- 2004-04-29 KR KR1020040029791A patent/KR100657212B1/en active IP Right Grant
-
2005
- 2005-04-27 EP EP05764804A patent/EP1740714A1/en not_active Withdrawn
- 2005-04-27 CN CNA200580013419XA patent/CN1946855A/en active Pending
- 2005-04-27 WO PCT/KR2005/001213 patent/WO2005111227A1/en not_active Application Discontinuation
- 2005-04-27 US US11/587,228 patent/US7485452B2/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4957867A (en) | 1986-05-29 | 1990-09-18 | Sumitomo Chemical Company, Limited | Production of cyclopentenones by enzyme resolution |
| US5108916A (en) | 1989-06-05 | 1992-04-28 | Rhone-Poulenc Rorer, S.A. | Process for stereoselectively hydrolyzing, transesterifying or esterifying with immobilized isozyme of lipase from candida rugosa |
| KR20000059531A (en) | 1999-03-04 | 2000-10-05 | 조생현 | Method for manufacturing the pirdo-benz-oxizine for optical a ativity |
| EP1408107A2 (en) | 2002-10-07 | 2004-04-14 | Daiso Co., Ltd. | Chlorohydrin and hydroxycarboxylic ester asymmetric hydrolase gene |
Non-Patent Citations (16)
| Title |
|---|
| Boaz, Neil W., Enzymatic Hydrolysis of Ethyl 3-Hydroxy-3-phenylpropanoate: Observations on an Enzyme Active-Site Model, J. Org. Chem. 57, 1992, pp. 4289-4292. |
| Bucciarelli et al., Enantioselective lipase-catalyzed acetylation of beta-lactam precursors of carbapenem antibiotics, J. Chem. Soc., Perkin Trans. 1, 1999, pp. 2489-2494. |
| Chin-Joe et al., Hydrolytic Activity in Baker's Yeast Limits the Yield of Asymmetric 3-Oxo Ester Reduction, Biotechnology and Bioengineering, 2000, vol. 69, No. 4, pp. 370-376. |
| Fishman et al., A Two-Step Enzymatic Resolution Process for Large-Scale Production of (S)- and (R)-Ethyl-3-Hydroxybutyrate, Biotechnology and Bioengineering, 2001, vol. 74, No. 3, pp. 256-263. |
| Hoff et al., Lipase-catalyzed resolution of esters of 4-chloro-3-hydroxybutanoic acid: effects of the alkoxy group and solvent on the enantiomeric ratio, Tetrahedron: Asymmetry 10, 1999, pp. 1401-1412. |
| Jayasinghe et al., The Yeast Medicated Reduction of Ethyl acetoacetate in Petroleum Ether, Tetrahedron Letters, 1993, vol. 34, No. 24, pp. 3849-3850. |
| Kataoka et al., Stereoselective reduction of ethyl 4-chloro-3-oxobutanoate by Escherichia coli transformant cells coexpressing the aldehyde reductase and glucose dehydrogenase genes, Appl. Microbiol Biotechnol, 51, 1999, pp. 486-490. |
| Lee et al., Preparation of alkyl (R)-(-)-3-hydroxybutyrate by acidic alcoholysis of poly-(R)-(-)-3-hydroxybutyrate, Enzyme and Microbial Technology 27, 2000, pp. 33-36. |
| Medson et al., The stereoselective preparation of beta-hydroxy esters using a yeast reduction in an organic solvent, Tetrahedron: Asymmetry, 1997, vol. 8, No. 7 , pp. 1049-1054. |
| Noyori et al., Asymmetric Hydrogenation of beta-Keto Carboxylic Esters. A Practical, Purely Chemical Access to beta-Hydroxy Esters in High Enantiomeric Purity, J. Am. Chem. Soc., 1987, 109, pp. 5856-5858. |
| Sharma et al, Journal of Molecular Catalysis B: Enzymatic, Enantio-reversal in Candida rugosa Lipase-catalyzed Esterification of 3-Hydroxybutyric Acid, 2000, 10, pp. 531-534. * |
| Shiosaki et al., Phosphorus-Containing Inhibitors of HMG-CoA Reductase. 1. 4-[(2-Arylethyl)hydroxyphosphinyl]-3-hydroxybutanoic Acids: A New Class of Cell-Selective Inhibitors of Cholesterol Biosynthesis, J. Med. Chem. 1990, 33, pp. 2952-2956. |
| Sugai et al., Enzymatic Preparation of Ethyl (S)-3-Hydroxybutanoate with a High Enantiomeric Excess, Agric. Biol. Chem, 1989, 53 (7), pp. 2009-2010. |
| Suzuki et al., Dual production of highly pure methyl (R)-4-chloro-3-hydroxybutyrate and (S)-3-hydroxy-gamma-butyrolactone with Enterobacter Sp., Enzyme and Microbial Technology 24, 1999, pp. 13-20. |
| Yamamoto et al., Synthesis of Ethyl (R)-4-Chloro-3-hydroxybutanoate with Recombinant Escherichia coli Cells Expressing (S)-Specific Secondary Alcohol Dehydrogenase, Biosci. Biotechnol. Biochem., 2002, 66 (2), pp. 481-483. |
| Zhou et al., Stereochemical Control of Yeast Reductions. 1. Asymmetric Synthesis of L-Carnitine, J. Am. Chem. Soc., 1983, 105, pp. 5925-5926. |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9163202B2 (en) | 2013-08-02 | 2015-10-20 | Eastman Chemical Company | Aqueous cleaning compositions including an alkyl 3-hydroxybutyrate |
| US9249378B2 (en) | 2013-08-02 | 2016-02-02 | Eastman Chemical Company | Aqueous cleaning compositions having enhanced properties |
| US9255059B2 (en) | 2013-08-02 | 2016-02-09 | Eastman Chemical Company | Method for producing an alkyl 3-hydroxybutyrate |
| US9255241B2 (en) | 2013-08-02 | 2016-02-09 | Eastman Chemical Company | Aqueous cleaning compositions including an alkyl 3-hydroxybutyrate |
| US9388114B2 (en) | 2013-08-02 | 2016-07-12 | Eastman Chemical Company | Compositions including an alkyl 3-hydroxybutyrate |
| US9506017B2 (en) | 2013-08-02 | 2016-11-29 | Eastman Chemical Company | Aqueous cleaning compositions including an alkyl 3-hydroxybutyrate |
| US10508070B1 (en) * | 2018-11-28 | 2019-12-17 | Shanghai Shine High International Trade Co., Ltd. | Method for preparing 3-hydroxybutyrate salts |
| WO2023278240A1 (en) | 2021-06-28 | 2023-01-05 | Phb Industrial S.A. | Methods to produce therapeutic formulations comprising hydroxybutirate and hydroxyvalerate, therapeutic formulations and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR100657212B1 (en) | 2006-12-14 |
| CN1946855A (en) | 2007-04-11 |
| US20080038802A1 (en) | 2008-02-14 |
| WO2005111227A1 (en) | 2005-11-24 |
| KR20050104481A (en) | 2005-11-03 |
| EP1740714A1 (en) | 2007-01-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7485452B2 (en) | Method of making optically active ester derivatives and their acids from racemic esters | |
| US9970043B2 (en) | Process for producing optically active 2-alkyl-1,1,3-trialkoxycarbonylpropane | |
| JP3794702B2 (en) | Enzymatic preparation of chiral-α-tertiary carboxylic esters | |
| US20100248337A1 (en) | PROCESS FOR THE PRODUCTION OF (s)-5-CHLORO-2-ISOPROPYLPENT-4-ENOIC ACID ESTERS | |
| Jeon et al. | Synthesis of alkyl (R)-lactates and alkyl (S, S)-O-lactyllactates by alcoholysis of rac-lactide using Novozym 435 | |
| US20030018048A1 (en) | Optically pure paroxetine precursors | |
| JP4042454B2 (en) | Process for producing optically active 3-methylglutaric acid monoester | |
| EP0451668B1 (en) | Process for the production of optically active alkyl 3-aryl-3-hydroxypropionates | |
| Romano et al. | A new chemoenzymatic synthesis of D-cloprostenol | |
| Yasohara et al. | Enzymatically enantioselective hydrolysis of prochiral 1, 3-diacyloxyglycerol derivatives | |
| JP3024299B2 (en) | Optically active cyclopentene alcohols, production method thereof and use thereof | |
| JP3732535B2 (en) | Process for producing optically active α-methylalkanedicarboxylic acid-ω-monoester and its enantiomer diester | |
| KR100758512B1 (en) | The method of preparing optically active 3-hydroxy-3-phenylpropionic acids and optically active 3-acyloxy-3-phenylpropionic acid by enzymatic method | |
| KR100748897B1 (en) | The method of making optically active 3-hydroxybutyric acid and their esters by enzymatic method | |
| JP2007117034A (en) | Method for producing optically active nipecotic acid compound | |
| US5986095A (en) | Enantioselective preparation of halophenyl alcohols and acylates | |
| JP4746019B2 (en) | Optically active β-cyanoisobutyric acid and process for producing the same | |
| JP2615768B2 (en) | Optically active carboxylic acid derivative and method for producing the same | |
| JP4565672B2 (en) | Optically active β-cyanoisobutyric acid and process for producing the same | |
| JP2003520018A (en) | Method for producing optically active 1-amino-4- (hydroxylmethyl) -cyclopent-2-ene derivative | |
| US20030109029A1 (en) | Process for the preparation of enantiomerically pure tertiary ss-hydroxycarboxylic acids or their esters | |
| JP2009263341A (en) | Method of manufacturing optically active nipecotic acid ester derivative | |
| JP2010505417A (en) | (3) Specific hydrolysis of N-unprotected (R) -esters of (3) -amino-3-arylpropionic acid esters | |
| JP2006014636A (en) | Method for producing acyl derivative | |
| JP2006061112A (en) | Method for producing optically active 2-(cyclopentylmethyl)-malonic acid monoester |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: ENZYTECH, LTD., KOREA, REPUBLIC OF Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HWANG, SOON OOK;CHUNG, SUN HO;REEL/FRAME:020142/0759 Effective date: 20061010 |
|
| FPAY | Fee payment |
Year of fee payment: 4 |
|
| REMI | Maintenance fee reminder mailed | ||
| LAPS | Lapse for failure to pay maintenance fees | ||
| STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
| FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20170203 |